Just take a break – relax. We humans like to do that. One might even be inclined to say that it is in our nature. If you take a closer look at the basis of our existence, the cells, then this idea is actually pretty close to molecular reality. The cells also take a break under certain circumstances or. stop sharing. This condition is referred to as cellular senescence.
Colloquially, these cells are often referred to as “undead” or “zombie cells”. And that's pretty close to the truth, because senescent cells are neither dead nor really alive. We deal with this relatively new scientific discovery in two articles. In the article about Senolytics we show you the scientific background and give you tips from science on how to get rid of senescent cells. This article is more about senescence and its role as one of the molecular Hallmarks of Aging.
Hayflick limit and telomeres – how do the “undead” arise?
Senescence (from Latin senescere; aging) plays an important role as the final stage of some processes in the body. In the previous articles on genomic instability and on mitochondrial dysfunction we have the Already got to know senescence. At a young age, senescence seems to be a kind of safe intermediate state for degenerate cells.
Cellular senescence is basically a stable arrest of the cell cycle. The first discoveries in this direction were made by scientists Leonard Hayflick and Paul Moorhead in the early 1960s. They found that human fibroblasts (connective tissue cells) in a culture divide a maximum of about 50 times before they suddenly stop and age.
What is common today was groundbreaking back then. In those long-ago days, the prevailing view in cell biology was that all cultured cells were immortal. Hayflick overthrew this dogma with his experiments and found that only cancer cells have this characteristic. The phenomenon of the division upper limit is called replicative senescence, or after its discoverer: Hayflick limit.
Currently we know that the senescence observed by Hayflick is caused by Telomere shortening. But there are also other stimuli, apart from telomere abrasion, that can trigger cellular senescence.
How do you measure senescence?
In addition to damage in the area of the telomeres, two other points in particular contribute to cellular senescence:non-telomeric DNA damage and the INK4/ ARF Locus on the DNA. Both occur in connection with chronological aging and are able to induce senescence - this has been proven in experiments. But how do you actually prove something like that?
First of all, it is important to note that Senescence cannot be measured directly. There is no laboratory parameter that produces a specific value after a blood sample has been taken. That's why researchers use so-called surrogate markers, which indirectly allow conclusions to be drawn. In the case of cellular senescence, DNA damage or senescence-associated β-galactosidase (SABG) are used as markers.
In a study from 2009, quantification was carried out in mice using these two parameters. This resulted in values of approximately 8% of senescent cells in young mice and approx. 17% in very old mice. If you look at the values by organ, similar values were found in skin, lungs and spleen. The researchers observed no changes in the heart, kidneys or muscle tissue.
This is exciting because it means that the extent of cellular senescence differs from tissue to tissue. In the case of tumor cells, for example, there is experimental evidence that they are strictly immune monitored and can subsequently be removed efficiently.
Aging and cellular senescence
We now know that the amount of senescent cells increases with age. This observation has been made in numerous studies. Why is this so? Without going into too much detail, there is a simple answer. too many of these “undead” cells are created or too few are broken down. The truth lies somewhere in the middle. However, the fact that aging research now has a new enemy image would be too short-sighted. The relationship is not as linear as it seems at first glance.
It is possible that the main purpose of senescence is quite different. Namely the prevention of the proliferation of damaged cells and the triggering of clearance by the immune system. Recall that DNA damage is a surrogate marker used to quantify senescence. Senescence is u.A a beneficial compensatory reaction to free tissue from broken and possibly even tumorous cells.
The prerequisite for this, however, is an effective cell replacement system. The senescent cells must first be removed and subsequently replaced in order for homeostasis or the balance in the tissue is maintained. Right here is the catch regarding aging.
This turnover system tends to become inefficient with increasing age, which is reflected in a lack of regenerative capacity of cells. This leads to the accumulation of senescent cells, which sooner or later worsen the damage and increase aging. However, the mere presence of a constantly increasing number of shut down cells is not decisive for this. Rather, the secretome is the culprit.
Secretome sounds mysterious at first, but it is “only” the entirety of all secreted substances in a cell. In the case of senescent cells, the secretome is particularly rich in inflammatory and destructive substances. In science it is called Senescence-Associated Secretory Phenotype (SASP). You can find out why exactly these inflammatory substances can cause problems in our article on Inflammaging.
Cell division as a recycling mechanism is strictly regulated in the body.
Mitogenic signaling – when something goes wrong during cell division
In addition to DNA damage, excessive mitogenic (cell division inducing) signal transmission is associated with senescence. Mitogen is easier to remember as MITOse GENerating. Mitosis is the process of cell division. There are a lot of these mitogenic or oncogenic (cancer-causing) changes. In response to these signals, senescence can be triggered in the cell. There are a number of mechanisms for this too, but the INK4a / ARF locus is unsurpassed in importance.
INK4a / ARF locus and p53 – what is hidden behind the abbreviations?
Don't be alarmed, the topic is not nearly as complicated as the title suggests. The level of p16INK4a (the protein generated based on the INK4a gene) is related to chronological age in all tissues analyzed, both in mice and humans. This colossal relevance is remarkable. The INK4a/ARF locus (location on DNA) was identified in a meta-analysis (highest scientific evidence) as the genomic location associated with the highest number of age-associated pathologies.
These include various types of cardiovascular disease, diabetes, glaucoma and Alzheimer's disease. p53 is another protein that induces senescence. In the nomenclature, “p” always stands for protein.
Did you know? The protein p16Ink4a is also detectable in senescent liver cells. An accumulation of these “zombie” cells over time contributes to the activation of pro-inflammatory signals from the cells, also known as the Senescence-Associated Secretory Phenotype (SASP), which can lead to increased inflammation and increased accumulation of fat in the liver. This process is often associated with non-alcoholic fatty liver disease (NAFLD).
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Opposite, but the same?
Due to the senescence-inducing function of p16INK4a and p53, researchers put forward the obvious hypothesis that the two proteins contribute to physiological aging . The age-promoting effect is therefore negligible when one considers the much more important advantages in tumor suppression. In fact, the topic is a little more complicated, as conflicting research results suggest.
In mice aged prematurely due to extensive and persistent cell damage elimination of p16INK4a and p53 achieved an improvement in the overall function of the organism. In another experiment, mice with a slight increase in both proteins had longer lifespans. This survival benefit was greater than a lower incidence of cancer would suggest.
The activation of the two proteins mentioned is therefore an advantageous reaction with regard to the development of tumors and thus cancer. This prevents the spread of mutated cells. But if damage becomes widespread and affects a large proportion of the cells in our body, then the body can no longer keep up: the ability to regenerate is exhausted. Under these conditions, INK4a/ARF activation is detrimental and aging is accelerated.
Cellular senescence – conclusion
Cellular senescence is a useful compensatory response to damage, but it can also accelerate aging and be detrimental to health if tissues can no longer recover adequately. Ultimately, there are twocontradictory intervention approaches derived from studies, both of which can make a contribution to longevity to date.
On the one hand, a tumor suppressor effect has positive effects on aging. On the other hand, the elimination of senescent cells in experiments shows a delay in age-related diseases. So the “undead” are not completely useless.
It's probably like always in nature. In the right balance, senescent cells are beneficial for our health because they give us e.g.b help to freeze broken cells so that they do not degenerate further. On the other hand, the number of senescent cells can increase so much with age and with it the inflammation that age-typical diseases are promoted.
The next article in this series will focus on the eighth hallmark of aging: Stem cell exhaustion.
